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Has an Alternative to Table Sugar Contributed to the C. Diff. Epidemic?

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Ice cream sundae

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Most of us know how hard it is to resist the creamy sweetness of ice cream. But it might surprise you to learn that, over the past 15 years or so, some makers of ice cream and many other processed foods—from pasta to ground beef products—have changed their recipes to swap out some of the table sugar (sucrose) with a sweetening/texturizing ingredient called trehalose that depresses the freezing point of food. Both sucrose and trehalose are “disaccharides.” Though they have different chemical linkages, both get broken down into glucose in the body. Now, comes word that this switch may be an important piece of a major medical puzzle: why Clostridium difficile (C. diff) has emerged as a leading cause of hospital-acquired infections.

A new study in the journal Nature indicates that trehalose-laden food may have helped fuel the recent epidemic spread of C. diff., which is a microbe that can cause life-threatening gastrointestinal distress, especially in older patients getting antibiotics and antacid medicines [1, 2]. In laboratory experiments, an NIH-funded team found that the two strains of C. diff. most likely to make people sick possess an unusual ability to thrive on trehalose, even at very low levels. And that’s not all: a diet containing trehalose significantly increased the severity of symptoms in a mouse model of C. diff. infection.

C. diff is a common bacterium that many people already have in their gut. In most cases, the bacterium doesn’t make people sick. The trouble often comes when taking antibiotics, especially in a hospital or nursing home. These drugs can upset the normal balance of healthy gut microbes, and because C. diff. is naturally resistant to many common antibiotics, this opportunistic microbe can multiply and produce toxins that cause inflammation and diarrhea.

Through the 1990s, C. diff. infections were mostly an occasional “nuisance” that would pass quickly. But in the 2000s, that changed. C. diff. infections became far more serious and common, soon emerging as the most frequent hospital-acquired infection in the United States. In 2011 alone, C. diff. sickened roughly a half-million Americans, and about 29,000 died [3].

The recent rise in C. diff. infections has been driven in large part by a particular group of bacterial strains, known collectively as RT027. Their spread may be explained in part by a mutation that lent the bugs resistance to certain antibiotics. But still unanswered was how this strain and another one called RT078 emerged so rapidly and became so prevalent.

An earlier study led by Robert Britton at Baylor College of Medicine, Houston, provided an important lead. He and his colleagues showed that the RT027 strains outcompeted many other C. diff. strains in cell culture and mouse studies [4].

To learn why in the new study, Britton and colleagues tested the strains’ ability to use various sugars that might be present in the gut to fuel their growth and give them a competitive advantage over other bacteria. Those studies suggested that RT027 strains have a special ability to grow on trehalose. In fact, further study of 21 different strains showed that the RT027 and RT078 strains, and only those strains, grow unusually well on a diet of trehalose.

Britton’s team found in the new study that RT027’s ability to grow on trehalose traces to a new mutation in the bacterial DNA. The change allows the bacterium to sense the sugar and produce an enzyme to metabolize it for food, even at extremely low concentrations. In contrast, RT078 is able to grow exceptionally well on low levels of trehalose, thanks to a cluster of four genes involved in metabolizing the sugar that were apparently acquired from another microbe. This shows the two C. diff strains have adapted to feed on trehalose in two completely different ways!

In mouse studies, Britton and colleagues found that a diet including trehalose makes infections with the RT027 strain more severe and sometimes deadly. The researchers also found that when trehalose is present, the epidemic C. diff. strains are not only more abundant, they produce more toxins for reasons that aren’t yet entirely clear. The team also has preliminary evidence from mice and people to suggest that enough dietary trehalose may make its way to the intestine to fuel the growth of those infectious strains.

Britton says the ability of these C. diff strains to grow on trehalose isn’t new. Strains of RT027 that efficiently metabolized trehalose were first isolated in the 1980s. Back then, people got most of their trehalose in small amounts from foods that naturally have it, such as mushrooms and shellfish.

What has changed is the recent addition of man-made trehalose into the food supply, often in large quantities. This shift was prompted by a new method to manufacture trehalose from cornstarch, which made the sugar much less costly. In 2000, FDA approved the sugar as a safe food additive. Trehalose quickly found its way into processed foods in the U.S. and around the world for its mild, flavor-enhancing sweetness and protection of frozen foods. In some store-bought ice creams, it’s found at concentrations of up to 11 percent.

What Britton and colleagues noticed is the more widespread use of manufactured trehalose coincided with early reports of C. diff. outbreaks. Those outbreaks popped up not only in the U.S., but also in countries all around the world where trehalose consumption increased. While more study is surely needed to nail down the possible connection, the circumstantial and experimental evidence has led Britton’s team to propose that widespread use of trehalose inadvertently played a key role in the recent emergence of C. diff infections.

This doesn’t mean that everyone needs to start worrying about trehalose. In fact, Britton says the sugar does have some advantages. For instance, because it’s harder to break down, trehalose doesn’t cause blood glucose to spike in the way some other sugars do.

Britton’s team continues to study the interaction between these C. diff. strains and trehalose. They are especially curious to learn more about how and why trehalose causes some C. diff. strains to produce more toxins in the gut. The findings certainly offer food for thought about the complex interplay between our diets, gut microbes, and health—and the unintended consequences that dietary changes might bring.

References:

[1] Dietary trehalose enhances virulence of epidemic Clostridium difficile. Collins J, Robinson C, Danhof H, Knetsch CW, van Leeuwen HC, Lawley TD, Auchtung JM, Britton RA. Nature. 2018 Jan 3.

[2] Evaluating the risk factors for hospital-onset Clostridium difficile infections in a large healthcare system. Watson T, Hickok J, Fraker S, Korwek K, Poland RE, Septimus E. Clin Infect Dis. 2017 Dec 20.

[3] Clostridium difficile infection. Centers for Disease Control and Prevention.

[4] Epidemic Clostridium difficile strains demonstrate increased competitive fitness compared to nonepidemic isolates. Robinson CD, Auchtung JM, Collins J, Britton RA. Infect Immun. 2014 Jul;82(7):2815-25.

Links:

Clostridium Difficile (National Institute of Allergy and Infectious Diseases/NIH)

Britton Lab (Baylor College of Medicine, Houston)

NIH Support: National Institute of Allergy and Infectious Diseases

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